TLR-driven early glycolytic reprogramming via the kinases TBK1-IKKɛ supports the anabolic demands of dendritic cell activation

Abstract

The ligation of Toll-like receptors (TLRs) leads to rapid activation of dendritic cells (DCs). However, the metabolic requirements that support this process remain poorly defined. We found that DC glycolytic flux increased within minutes of exposure to TLR agonists and that this served an essential role in supporting the de novo synthesis of fatty acids for the expansion of the endoplasmic reticulum and Golgi required for the production and secretion of proteins that are integral to DC activation. Signaling via the kinases TBK1, IKKɛ and Akt was essential for the TLR-induced increase in glycolysis by promoting the association of the glycolytic enzyme HK-II with mitochondria. In summary, we identified the rapid induction of glycolysis as an integral component of TLR signaling that is essential for the anabolic demands of the activation and function of DCs.

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Figure 1: TLR ligation induces a rapid increase in glycolytic metabolism in DCs.
Figure 2: The glycolytic burst is required for the activation and function of DCs.
Figure 3: TLR-induced activation of DCs depends on the flux of glucose-derived carbon into the TCA cycle.
Figure 4: TLR-induced activation of DCs requires de novo synthesis of fatty acids supported by glycolysis.
Figure 5: The PPP supports the accumulation of lipids in DCs stimulated via TLRs.
Figure 6: The TLR-driven glycolytic burst is dependent on TBK1-IKKɛ and Akt.
Figure 7: The TLR-induced glycolytic burst and activation of DCs are dependent on the Akt-driven association of HK-II with mitochondria.
Figure 8: DCs rely on a rapid increase in glycolytic metabolism and fatty-acid synthesis for their activation and function in vivo.

References

  1. 1

    Satpathy, A.T., Wu, X., Albring, J.C. & Murphy, K.M. Re(de)fining the dendritic cell lineage. Nat. Immunol. 13, 1145–1154 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. 2

    Joffre, O., Nolte, M.A., Sporri, R. & Reis e Sousa, C. Inflammatory signals in dendritic cell activation and the induction of adaptive immunity. Immunol. Rev. 227, 234–247 (2009).

    CAS  PubMed  Google Scholar 

  3. 3

    Pearce, E.L. & Pearce, E.J. Metabolic pathways in immune cell activation and quiescence. Immunity 38, 633–643 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4

    Krawczyk, C.M. et al. Toll-like receptor-induced changes in glycolytic metabolism regulate dendritic cell activation. Blood 115, 4742–4749 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5

    Jantsch, J. et al. Hypoxia and hypoxia-inducible factor-1α modulate lipopolysaccharide-induced dendritic cell activation and function. J. Immunol. 180, 4697–4705 (2008).

    CAS  PubMed  Google Scholar 

  6. 6

    Everts, B. et al. Commitment to glycolysis sustains survival of NO-producing inflammatory dendritic cells. Blood 120, 1422–1431 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7

    Cleeter, M.W., Cooper, J.M., Darley-Usmar, V.M., Moncada, S. & Schapira, A.H. Reversible inhibition of cytochrome c oxidase, the terminal enzyme of the mitochondrial respiratory chain, by nitric oxide. Implications for neurodegenerative diseases. FEBS Lett. 345, 50–54 (1994).

    CAS  PubMed  Google Scholar 

  8. 8

    Grossbard, L. & Schimke, R.T. Multiple hexokinases of rat tissues. Purification and comparison of soluble forms. J. Biol. Chem. 241, 3546–3560 (1966).

    CAS  PubMed  Google Scholar 

  9. 9

    Chang, C.H. et al. Posttranscriptional control of T cell effector function by aerobic glycolysis. Cell 153, 1239–1251 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10

    Khabar, K.S. The AU-rich transcriptome: more than interferons and cytokines, and its role in disease. J. Interferon Cytokine Res. 25, 1–10 (2005).

    CAS  PubMed  Google Scholar 

  11. 11

    Wagner, A. Energy constraints on the evolution of gene expression. Mol. Biol. Evol. 22, 1365–1374 (2005).

    CAS  PubMed  Google Scholar 

  12. 12

    Brand, M.D. & Nicholls, D.G. Assessing mitochondrial dysfunction in cells. Biochem. J. 435, 297–312 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13

    van der Windt, G.J. et al. Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development. Immunity 36, 68–78 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14

    Hatzivassiliou, G. et al. ATP citrate lyase inhibition can suppress tumor cell growth. Cancer Cell 8, 311–321 (2005).

    CAS  PubMed  Google Scholar 

  15. 15

    Palmieri, F. The mitochondrial transporter family (SLC25): physiological and pathological implications. Pflugers Arch. 447, 689–709 (2004).

    CAS  PubMed  Google Scholar 

  16. 16

    Jensen-Urstad, A.P. & Semenkovich, C.F. Fatty acid synthase and liver triglyceride metabolism: housekeeper or messenger? Biochim. Biophys. Acta 1821, 747–753 (2012).

    CAS  PubMed  Google Scholar 

  17. 17

    Nagy, L., Szanto, A., Szatmari, I. & Szeles, L. Nuclear hormone receptors enable macrophages and dendritic cells to sense their lipid environment and shape their immune response. Physiol. Rev. 92, 739–789 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

    Ward, P.S. & Thompson, C.B. Signaling in control of cell growth and metabolism. Cold Spring Harb. Perspect. Biol. 4, a006783 (2012).

    PubMed  PubMed Central  Google Scholar 

  19. 19

    Fayard, E., Xue, G., Parcellier, A., Bozulic, L. & Hemmings, B.A. Protein kinase B (PKB/Akt), a key mediator of the PI3K signaling pathway. Curr. Top. Microbiol. Immunol. 346, 31–56 (2010).

    CAS  PubMed  Google Scholar 

  20. 20

    Xie, X. et al. IκB kinase epsilon and TANK-binding kinase 1 activate AKT by direct phosphorylation. Proc. Natl. Acad. Sci. USA 108, 6474–6479 (2011).

    CAS  PubMed  Google Scholar 

  21. 21

    Clark, K., Takeuchi, O., Akira, S. & Cohen, P. The TRAF-associated protein TANK facilitates cross-talk within the IκB kinase family during Toll-like receptor signaling. Proc. Natl. Acad. Sci. USA 108, 17093–17098 (2011).

    CAS  Google Scholar 

  22. 22

    Guo, J.P., Coppola, D. & Cheng, J.Q. IKBKE protein activates Akt independent of phosphatidylinositol 3-kinase/PDK1/mTORC2 and the pleckstrin homology domain to sustain malignant transformation. J. Biol. Chem. 286, 37389–37398 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    Ou, Y.H. et al. TBK1 directly engages Akt/PKB survival signaling to support oncogenic transformation. Mol. Cell 41, 458–470 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24

    Reilly, S.M. et al. An inhibitor of the protein kinases TBK1 and IKK-varɛ improves obesity-related metabolic dysfunctions in mice. Nat. Med. 19, 313–321 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    John, S., Weiss, J.N. & Ribalet, B. Subcellular localization of hexokinases I and II directs the metabolic fate of glucose. PLoS ONE 6, e17674 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

    Miyamoto, S., Murphy, A.N. & Brown, J.H. Akt mediates mitochondrial protection in cardiomyocytes through phosphorylation of mitochondrial hexokinase-II. Cell Death Differ. 15, 521–529 (2008).

    CAS  PubMed  Google Scholar 

  27. 27

    Majewski, N. et al. Hexokinase-mitochondria interaction mediated by Akt is required to inhibit apoptosis in the presence or absence of Bax and Bak. Mol. Cell 16, 819–830 (2004).

    CAS  PubMed  Google Scholar 

  28. 28

    van der Windt, G.J. et al. CD8 memory T cells have a bioenergetic advantage that underlies their rapid recall ability. Proc. Natl. Acad. Sci. USA 110, 14336–14341 (2013).

    CAS  PubMed  Google Scholar 

  29. 29

    Sakamoto, K. & Holman, G.D. Emerging role for AS160/TBC1D4 and TBC1D1 in the regulation of GLUT4 traffic. Am. J. Physiol. Endocrinol. Metab. 295, E29–E37 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30

    Mor, I., Cheung, E.C. & Vousden, K.H. Control of glycolysis through regulation of PFK1: old friends and recent additions. Cold Spring Harb. Symp. Quant. Biol. 76, 211–216 (2011).

    CAS  PubMed  Google Scholar 

  31. 31

    Robey, R.B. & Hay, N. Is Akt the “Warburg kinase”?-Akt-energy metabolism interactions and oncogenesis. Semin. Cancer Biol. 19, 25–31 (2009).

    CAS  PubMed  Google Scholar 

  32. 32

    Nicolaou, G., Goodall, A.H. & Erridge, C. Diverse bacteria promote macrophage foam cell formation via Toll-like receptor-dependent lipid body biosynthesis. J. Atheroscler. Thromb. 19, 137–148 (2012).

    CAS  PubMed  Google Scholar 

  33. 33

    Funk, J.L., Feingold, K.R., Moser, A.H. & Grunfeld, C. Lipopolysaccharide stimulation of RAW 264.7 macrophages induces lipid accumulation and foam cell formation. Atherosclerosis 98, 67–82 (1993).

    CAS  PubMed  Google Scholar 

  34. 34

    Feingold, K.R. et al. Mechanisms of triglyceride accumulation in activated macrophages. J. Leukoc. Biol. 92, 829–839 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Im, S.S. et al. Linking lipid metabolism to the innate immune response in macrophages through sterol regulatory element binding protein-1a. Cell Metab. 13, 540–549 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    Rakoff-Nahoum, S. & Medzhitov, R. Toll-like receptors and cancer. Nat. Rev. Cancer 9, 57–63 (2009).

    CAS  PubMed  Google Scholar 

  37. 37

    Ibrahim, J. et al. Dendritic cell populations with different concentrations of lipid regulate tolerance and immunity in mouse and human liver. Gastroenterology 143, 1061–1072 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Infantino, V. et al. The mitochondrial citrate carrier: a new player in inflammation. Biochem. J. 438, 433–436 (2011).

    CAS  PubMed  Google Scholar 

  39. 39

    Tannahill, G.M. et al. Succinate is an inflammatory signal that induces IL-1β through HIF-1α. Nature 496, 238–242 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40

    Stiles, B.L. PI-3-K and AKT: onto the mitochondria. Adv. Drug Deliv. Rev. 61, 1276–1282 (2009).

    CAS  PubMed  Google Scholar 

  41. 41

    Abu-Hamad, S., Zaid, H., Israelson, A., Nahon, E. & Shoshan-Barmatz, V. Hexokinase-I protection against apoptotic cell death is mediated via interaction with the voltage-dependent anion channel-1: mapping the site of binding. J. Biol. Chem. 283, 13482–13490 (2008).

    CAS  PubMed  Google Scholar 

  42. 42

    Jin, H.K. et al. Rapamycin down-regulates inducible nitric oxide synthase by inducing proteasomal degradation. Biol. Pharm. Bull. 32, 988–992 (2009).

    CAS  PubMed  Google Scholar 

  43. 43

    Lisi, L., Navarra, P., Feinstein, D.L. & Dello Russo, C. The mTOR kinase inhibitor rapamycin decreases iNOS mRNA stability in astrocytes. J. Neuroinflammation 8, 1 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Trinchieri, G. Type I interferon: friend or foe? J. Exp. Med. 207, 2053–2063 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45

    Lutz, M.B. et al. An advanced culture method for generating large quantities of highly pure dendritic cells from mouse bone marrow. J. Immunol. Methods 223, 77–92 (1999).

    CAS  Google Scholar 

  46. 46

    Faubert, B. et al. AMPK is a negative regulator of the Warburg effect and suppresses tumor growth in vivo. Cell Metab. 17, 113–124 10.1016/j.cmet.2012.12.001(2013).

    CAS  Article  PubMed  Google Scholar 

  47. 47

    Xu, Q., Vu, H., Liu, L., Wang, T.C. & Schaefer, W.H. Metabolic profiles show specific mitochondrial toxicities in vitro in myotube cells. J. Biomol. NMR 49, 207–219 (2011).

    CAS  PubMed  Google Scholar 

  48. 48

    Pearce, E.L. et al. Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature 460, 103–107 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank members of the Pearce laboratory for discussions; H. Virgin for support of the 14C-glucose–tracing experiments; W. Beatty and the Molecular Microbiology Imaging Facility for technical assistance with electron microscopy; and G. Bridon and B. Faubert for help with the glucose-tracing experiments. Some observations reported here were made while B.E., E.A., T.C.F., G.J.W.v.d.W., E.L.P. and E.J.P. were at the Trudeau Institute; we thank the institute for its support during that time. Supported by the US National Institutes of Health (AI53825 and CA164062 to E.J.P.; AI091965 and CA158823 to E.L.P.; and AI049823 to E.A.), the Netherlands Organisation for Scientific Research (B.E. and G.J.W.v.d.W.) and The Arthritis Society of Canada (R.G.J.).

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B.E., E.A., S.C.-C.H., C.-H.C., G.J.W.v.d.W., R.G.J., E.L.P. and E.J.P. designed experiments; B.E., E.A., S.C.-C.H., C.-H.C., A.M.S., W.Y.L., V.R., T.C.F. and J.B. did experiments. B.E., E.A., S.C.-C.H., J.B., R.G.J., M.N.A., E.L.P. and E.J.P. analyzed data; and B.E. and E.J.P. wrote the paper.

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Correspondence to Edward J Pearce.

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Integrated supplementary information

Supplementary Figure 1 GM-DCs display an early iNOS-independent and a late iNOS-dependent increase in glycolysis in response to LPS.

GM-DCs were seeded in a Seahorse XF-96 analyzer and ECAR was determined at indicated times after LPS stimulation in the presence or absence of NOS inhibitor SEITU. Data represent mean ±SEM of triplicate wells. One representative experiment out of 3 is shown.

Supplementary Figure 2 Effects of 2-DG on TLR-induced cytokine production, on binding of GAPDH to cytokine transcripts, on cell death and on activation of Flt3L-DCs.

(a,c) Nos2-/- GM-DCs were stimulated with LPS in the presence or absence of 2-DG and after 6 h (a) culture supernatants were analyzed for indicated cytokines (c) and cell death was determined by flow cytometry. (a) Bars represent mean ± SEM of triplicate wells. (b) GM-DCs were stimulated with LPS in the presence or absence of 2-DG and after 3 h GAPDH was immunoprecipitated and binding of mRNA of indicated genes to GAPDH was quantified by RT-qPCR. Bars represent mean ±SEM of 3 independent experiments. (d) SIRPα+ and CD24+ DCs were flow cytometry-sorted from Flt3L-BM cultures, stimulated with indicated TLR agonists in the presence or absence of 2-DG and 16 h later expression of indicated surface marker was determined by flow cytometry. Bars represent mean ±SEM of 3 independent experiments. (a,c) One representative experiment out of 2 is shown. *, P < 0.05; **, P < 0.01; ***, P < 0.001

Supplementary Figure 3 Glycolytic ATP is not essential for DC activation.

(a) Relative ATP levels are shown in GM-DCs at indicated time points following LPS stimulation. Data represent mean ±SEM of duplicate wells. (b) GM-DCs were analyzed as in Fig. 1a in response to treatment with LPS following pretreatment with LDHA inhibitor oxamate. Data represent triplicate wells and are shown as mean ±SEM. (c,d) GM-DCs, pretreated with oxamate, were analyzed for expression of indicated markers (c) or cytokines (d) 6 h after LPS stimulation by flow cytometry, based on surface or intracellular staining, respectively. (c) Expression levels are shown relative to LPS-stimulated DCs. (c) Bars represent at least 3 independent experiments ±SEM. (d) Grey solid and black open histograms represent unstimulated and stimulated cells, respectively. (a,b,d) One representative experiment out of 3 is shown.

Supplementary Figure 4 Glycolysis-derived carbon, but not that of glutaminolysis or FA oxidation, is required for DC activation.

(a,b) GM-DCs were stimulated with LPS in the presence or absence pyruvate carrier inhibitor α-cyanocinnamate (αCC), CPT1a inhibitor etomoxir (eto) or glutaminase inhibitor 6-Diazo-5-oxo-L-norleucine (DON) and 6 h later expression of indicated surface markers (a) and indicated cytokines (b) was determined by flow cytometry. (a) Data are shown relative to LPS-stimulated DCs and bars represent mean ±SEM of 3 independent experiments. (b) Grey solid and black open histograms represent unstimulated and stimulated cells, respectively. (c) GM-DCs were transduced with retroviral vectors expressing hairpins (hp) or over-expressing constructs (oe) of PDK1 and LDHA or their respective controls. DCs expressing huCD8 and GFP, as reporters for transduction, were analyzed for surface expression of indicated markers after stimulation with medium or LPS for 24 h. (b,c) One representative experiment out of 3 is shown. *, P < 0.01

Supplementary Figure 5 Mitochondrial ATP is not required for DC activation.

(a,b) GM-DCs, pretreated with oligomycin, were analyzed for expression of indicated markers (a) or cytokines (b) 6 h after LPS stimulation by flow cytometry, based on surface or intracellular staining, respectively. (a) Expression levels are shown relative to LPS-stimulated DCs and bars represent mean ±SEM of 4 independent experiments. (b) Grey solid and black open histograms represent unstimulated and stimulated cells, respectively. (c) GM-DCs were stimulated with LPS in the presence or absence of C75 and after 6 h PGE2 levels were determined in culture supernatants. Bars represent mean ±SEM of duplicates (b,c) (d,e) GM-DCs, pretreated with C75, were stimulated with LPS in the presence or absence of rosiglitazone (Rgz) and 6 h later analyzed for expression of indicated markers (d) or cytokines (e) by flow cytometry, based on surface or intracellular staining respectively. (b,e) Grey solid and black open histograms represent unstimulated and stimulated cells, respectively. One representative experiment out of (b) 4 or (c,d,e) 2 is shown. *, P < 0.05

Supplementary Figure 6 TLR-driven Akt activation and ECAR burst is TBK1-IKKɛ dependent but mTOR and PI(3)K independent.

(a) GM-DCs were analyzed for real-time changes in ECAR in response to stimulation with LPS following pretreatment with Akt inhibitor Akt1/2 VIII, mTORC1 inhibitor rapamycin (rap) or PI(3)K inhibitor wortmannin (WM). ECAR is shown relative to basal levels prior to inhibitor incubation, which is set to 1. (b) GM-DCs were pre-incubated with indicated inhibitors and stimulated with or without LPS for 15 minutes after which Akt phosphorylation was assessed by flow cytometry. (c) GM-DCs were pre-incubated with Akt inhibitors triciribine (Tric) and Akt1/2 VIII, TBK1-IKKɛ inhibitor BX795 (BX), rapamycin or wortmannin, and stimulated with LPS for 15 minutes after which phosphorylation of indicated proteins were assessed by immunnoblot. (d) GM-DCs were stimulated with TLR2 agonist Pam3CSK4 and analyzed for TBK1 phosphorylation by immunoblot. (e) GM-DCs were stimulated as in (c) and analyzed for TBK1 phosphorylation. (f) WT or Ikbke-/-GM-DCs were transduced with retroviral vectors expressing a control or TBK1 hairpin, sorted based on huCD8 expression as a reporter for transduction and analyzed for Akt phosphorylation by flow cytometry 15 min after LPS stimulation. (g) GM-DCs were analyzed for real-time changes in ECAR in response to stimulation with LPS following pretreatment with Akt inhibitor triciribine or TBK1-IKKɛ inhibitor Amlexanox (Amx). ECAR is shown relative to basal levels prior to inhibitor incubation, which is set to 1. Data represent are shown as mean ±SEM (a,g) triplicate or (f) duplicate wells. One representative experiment out of (b) 5, (a,c,e) 3 or (d,f,g) 2 is shown.

Supplementary Figure 7 Chemical dissociation of HK from mitochondria impairs glycolytic flux and DC activation.

(a) Following pretreatment with Akt1/2 VIII, GM-DCs were stimulated with LPS for 1 h after which HK activity was determined. Bars represent mean ±SEM of duplicates. (b) GM-DCs were treated with clotrimazole (CLT), a drug that dissociates HK from mitochondria, and cytosolic and mitochondrial fractions were analyzed for the presence of HK-II. (c) Following pretreatment with CLT, GM-DCs were stimulated with LPS for 1 h after which HK activity was determined. Bars represent mean ±SEM of 3 independent. (d) GM-DCs were analyzed as in Fig. 1a following pretreatment with CLT. Data represent mean ±SEM of triplicate wells. (e,f) GM-DCs, pretreated with CLT, were stimulated with LPS for 6 h and subsequently analyzed as in Fig. 2b,c. (e) Bars represent mean ±SEM of 3 independent experiments. (f) Grey solid and black open histograms represent unstimulated and stimulated cells, respectively. One representative experiment out of (a,b) 2 or (d,f) 3 is shown. *, P < 0.05

Supplementary Figure 8 TLR-induced early glycolytic burst is not dependent on increased GLUT1 translocation to the cell surface, PFK-2 isoforms PFKFB2 and PFKFB3, mTORC1 or HIF-1α.

(a) Expression of glucose transporter genes in GM-DCs (derived from public database GSE17721). Relative expression is shown. (b) GLUT1 surface expression on GM-DCs was determined by flow cytometry following stimulation with LPS for 1 or 24 h. (c) mRNA expression levels of indicated genes were determined by RT-qPCR of GM-DCs transduced with retroviral vectors expressing hairpins (hp) to Pfkfb2 and Pfkfb3 or a control. Relative expression is shown. (d) Sorted transduced DCs were analyzed as in Fig. 1a. Data are representative of triplicate wells and are shown as mean ±SEM. (e,f) sorted CD11c+ GM-DCs derived from Rptorfl/fl Itgaxcre (CD11cΔraptor) or Rptorfl/fl (CD11cWT) mice were analyzed (e) for indicated proteins by immunoblot and (f) analyzed as in Fig. 1a. (g) GM-DCs were stimulated with LPS for 1 h and analyzed for indicated proteins by immunoblot. (h) Global transcription was determined in GM-DCs by detection of incorporation of nucleotide homolog ethylene uridine (EU) by flow cytometry following a 3 h pulse in the presence or absence of Actinomycin-D (ActD). (i) GM-DCs were analyzed as in Fig. 1a following preincubation with ActD. (j) mRNA expression of Hif1a was determined as in (c). (k) Sorted transduced DCs were analyzed as in Fig. 1a. Data represent mean ±SEM from (d,f,I,k) triplicate wells or (a,c) 2 or (j) 3 experiments. One representative experiment out of (e,f,k) 2 or (b,d,g,h,i) 3 is shown. *, P < 0.05; **, P < 0.01.

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Everts, B., Amiel, E., Huang, SC. et al. TLR-driven early glycolytic reprogramming via the kinases TBK1-IKKɛ supports the anabolic demands of dendritic cell activation. Nat Immunol 15, 323–332 (2014). https://doi.org/10.1038/ni.2833

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